Endothelial dysfunction is recognized as a key process in the development and progression of chronic kidney disease (CKD). Additionally, endothelial dysfunction is thought to contribute to the increased risk for CVD in this population. Impaired endothelial function is a primary event in the development of atherosclerosis and it is now recognized that that CVD is the most important cause of morbidity and mortality in CKD. An understanding of the mechanisms responsible for endothelial dysfunction in CKD is important for improving renal and cardiovascular outcomes. Oxidative stress is elevated in patients with CKD and those on hemodialysis (HD) and has the potential to impair endothelial function. Thus, endothelial dysfunction secondary to oxidative stress may be a mechanism by which renal function deteriorates and CVD risk increases in CKD. Investigations into the mechanism(s) of endothelial dysfunction in CKD have the potential to lead to development of therapeutic measures aimed at maintaining renal function and reducing cardiovascular risk in CKD. The focus of this proposal is to elucidate whether oxidative stress plays a mechanistic role in endothelial dysfunction in patients with moderate to severe CKD before they require dialysis. The first goal of this proposal is to investigate whether oxidative stress plays a mechanistic role in impairing endothelial function early in the progression of CKD by using an acute infusion of ascorbic acid. We will use an infusion of ascorbic acid and measurement of endothelial dependent flow mediated dilation (FMD) to answer this question. We hypothesize that FMD will be lower in CKD patients compared to healthy control subjects but will be improved during infusion of ascorbic acid. Our second goal is to identify biological markers that predict an individual patient's endothelial response to ascorbic acid infusion in order to identify patients who may require more aggressive intervention to reduce oxidative stress. We hypothesize that oxidized low density lipoproteins, 8-isoprostane F2 , myeloperoxidase, and asymmetric a dimethylarginine will predict the magnitude of vascular response to ascorbic acid infusion in CKD. These studies are innovative in that our proposed ascorbic acid infusion protocol will generate new information regarding the role of oxidative stress in impairing endothelial function in CKD. The purpose of this project is to investigate the mechanisms of vascular dysfunction in chronic kidney disease in order to better understand the facors that lead to a progression of renal disease and the development of cardiovascular disease. Understanding these mechanisms may aid in the evaluation of therapies aimed at improving vascular function in chronic kidney disease. [unreadable] [unreadable] [unreadable]